diarhea chemo drug induced ncbi

Chemotherapy-induced diarrhea:pathophysiology, frequency andguideline-based management

Alexander Stein, Wieland Voigt and Karin Jordan

Abstract: Diarrhea is one of the main drawbacks for cancer patients. Possible etiologies couldbe radiotherapy, chemotherapeutic agents, decreased physical performance, graft versus hostdisease and infections. Chemotherapy-induced diarrhea (CID) is a common problem, especiallyin patients with advanced cancer. The incidence of CID has been reported to be as high as5080% of treated patients (30% CTC grade 35), especially with 5-fluorouracil bolus orsome combination therapies of irinotecan and fluoropyrimidines (IFL, XELIRI). Regardless ofthe molecular targeted approach of tyrosine kinase inhibitors and antibodies, diarrhea is acommon side effect in up to 60% of patients with up to 10% having severe diarrhea.Furthermore, the underlying pathophysiology is still under investigation. Despite the number ofclinical trials evaluating therapeutic or prophylactic measures in CID, there are just threedrugs recommended in current guidelines: loperamide, deodorized tincture of opium andoctreotide. Newer strategies and more effective agents are being developed to reduce themorbidity and mortality associated with CID. Recent research focusing on the prophylactic useof antibiotics, budesonide, probiotics or activated charcoal still have to define the role of thesedrugs in the routine clinical setting. Whereas therapeutic management and clinical work-up ofpatients presenting with diarrhea after chemotherapy are rather well defined, prediction andprevention of CID is an evolving field. Current research focuses on establishing predictivefactors for CID like uridine diphosphate glucuronosyltransferase-1A1 polymorphisms for iri-notecan or dihydropyrimidine-dehydrogenase insufficiency for fluoropyrimidines.

Keywords: chemotherapy-induced diarrhea, frequency, irinotecan, loperamide, octreotide,pathophysiology, prevention management

IntroductionIn oncological patients, diarrhea can occur in

several different situations. Possible etiologies

could be radiotherapy, chemotherapeutic

agents, decreased physical performance, graft

versus host disease and infections. Careful analy-

sis of the causative agent can lead to a more accu-

rate management and early intervention possibly

helps to prevent severe complications that may be

irreversible [Davila and Bresalier, 2008; Vincenzi

et al. 2008]. In particular, chemotherapy-induced

diarrhea (CID) is a common problem in patients

with advanced cancer and has to be carefully dif-

ferentiated from other causes of diarrhea [Gibson

and Stringer, 2009].

Chemotherapy-induced diarrheaCID can occur in 5080% of patients dependingon the chemotherapy regimen [Benson et al.

2004; Gibson and Stringer, 2009]. A review of

early toxic deaths occurring in two National

Cancer Institute-sponsored cooperative group

trials of irinotecan plus high-dose fluorouracil

and leucovorin for advanced colorectal cancer

has led to the recognition of a life-threatening

gastrointestinal syndrome and highlighted the

need for vigilant monitoring and aggressive ther-

apy for this serious complication [Conti et al.

1996; Arbuckle et al. 2000; Saltz et al. 2000].

CID can cause depletion of fluids and electro-

lytes, malnutrition, dehydration and hospitaliza-

tion, all of which can lead to cardiovascular

http://tam.sagepub.com 51

Therapeutic Advances in Medical Oncology Review

Ther Adv Med Oncol

(2010) 2(1) 5163

DOI: 10.1177/1758834009355164

! The Author(s), 2010.Reprints and permissions:http://www.sagepub.co.uk/journalsPermissions.nav

Correspondence to:Alexander Stein, MDDepartment of InternalMedicine IV, Oncology/Hematology/Hemostaseology,Martin-Luther-UniversityHalle/Wittenberg,Ernst-Grube-Str. 40,06120 Halle/Saale,[email protected]

Wieland VoigtKarin JordanDepartment of InternalMedicine IV, Oncology/Hematology/Hemostaseology,Martin-Luther-UniversityHalle/Wittenberg,Ernst-Grube-Str. 40,06120 Halle/Saale,Germany

compromise and death. In addition, diarrhea can

interfere with and detract from cancer treatment

by causing dosing delays or reductions which

may have an impact on survival [Engelking

et al. 1998; Ippoliti, 1998]. Therapeutic agents

commonly causing diarrhea include

5-fluorouracil (5-FU), capecitabine and irinote-

can (CPT-11) [Benson et al. 2004; Keefe et al.

2004]. Usually it is a dose-related adverse effect

and may be associated with other features of tox-

icity. CID appears to be a multifactorial process

whereby acute damage to the intestinal mucosa

(including loss of intestinal epithelium, superfi-

cial necrosis and inflammation of the bowel

wall) causes an imbalance between absorption

and secretion in the small bowel [Keefe et al.

2000; Keefe, 2007; Gibson and Stringer, 2009].

FrequencyThe frequency of CID depends on the drug and

schedule, with the highest rate of diarrhea occur-

ring with weekly irinotecan and bolus 5-FU

(Table 1). Late diarrhea from irinotecan occurs

at all dose levels, whereas early-onset diarrhea

(24 hours after administration) is dose depen-dent, developing in up to 10% of patients (grade

3/4). The median time to onset of late diarrhea is

about 6 days with the 350mg/m2 every 3 weeks

schedule and 11 days with the weekly schedule

(125mg/m2).

Fluoropyrimidines have also been associated with

severe diarrhea. Both the therapeutic efficacy and

frequency of diarrhea associated with 5-FU are

increased when given with leucovorin (LV).

Clinical manifestations and evaluationCID can be debilitating and, in some cases, life

threatening. Findings in such patients include

volume depletion, renal failure, and electrolyte

disorders such as metabolic acidosis and depend-

ing upon water intake, hyponatremia (increased

water intake that cannot be excreted because of

the hypovolemic stimulus to the release of anti-

diuretic hormone) or hypernatremia (insufficient

water intake to replace losses) [Benson et al.

2004; Maroun et al. 2007].

Diagnosis of CID begins with a history to deter-

mine the severity according to the NCI CTC

grades (recently updated National Cancer

Institute Common Toxicity Criteria, Table 2).

The volume and duration of diarrhea should

also be determined, and the history should

include questions concerning foods or drugs

that might play a contributory role.

It should also be considered that other factors

can contribute to diarrhea in cancer patients trea-

ted with 5-FU or irinotecan. These include intes-

tinal infection (e.g. Clostridium difficile), radiation,

and a history of prior intestinal resection [Davila

and Bresalier, 2008; Vincenzi et al. 2008].

Irinotecan-induced diarrheaIrinotecan is frequently used in first- and

second-line treatment of metastatic colorectal

cancer [Saltz et al. 2000, 2007; Hurwitz et al.

2004; Jordan et al. 2004; Van Cutsem et al.

2009]. Regardless of its schedule of

Table 1. Rates of grade 3/4 diarrhea (CTC grades) for different therapeutic agents and combinations.

Agent Grade 3/4 diarrhea

Chemotherapy Single agent Combination therapy5-FU (bolus) 32% (G3) 26% XELIRI5-FU (CI) 613% 2528% IFL (bolus)irinotecan (late diarrhea) 1622% 1114% FOLFIRI (bolus/CI)capecitabine 11%docetaxel/paclitaxel 4% 14% docetaxel + capecitabine

19% DCFTargeted agentsanti-EGFR-antibodies 12% 15% cetuximab +FOLFIRIanti-EGFR-TKI 69% 13% lapatinib + capecitabine

15% lapatinib + paclitaxel6% erlotinib + gemcitabine

sorafenib/sunitinib 28% (G3)m-TOR inhibitors 14% (G3)

5-FU, 5-fluorouracil; DCF, docetaxel + cisplatin + 5-FU; EGFR, epidermal growth factor receptor; FOLFIRI,irinotecan + leucovorin + 5-FU; IFL, irinotecan + leucovorin + 5-FU; m-TOR, mammalian target of rapamycin; TKI, tyrosinekinase inhibitor; XELIRI, irinotecan + capecitabine.

Therapeutic Advances in Medical Oncology 2 (1)

52 http://tam.sagepub.com

administration, myelosuppression and delayed-

type diarrhea are the most common side effects

[Davila and Bresalier, 2008].

Irinotecan can cause acute diarrhea (immediately

after drug administration) or delayed diarrhea.

Immediate-onset diarrhea is caused by acute cho-

linergic properties and is often accompanied by

other symptoms of cholinergic excess, including

abdominal cramping, rhinitis, lacrimation, and

salivation. The mean duration of symptoms is

30 minutes and they usually respond rapidly to

atropine. Delayed-type diarrhea is defined as

diarrhea occurring more than 24 hours after

administration of irinotecan and is noncumula-

tive and occurs at all dose levels.

Main clinical predictive factors for irinotecan-

related diarrhea are weekly administration, poor

performance status, high serum creatinine levels,

prior abdominopelvic irradiation, low leukocyte

counts, age over 70 years, Gilbert syndrome

and Crigler-Najjar syndrome type 1 [Vincenzi

et al. 2008].

Pathophysiology of irinotecan-induced diarrheaIrinotecan is converted by hepatic and peripheral

carboxylesterase to its active metabolite

7-ethyl-10-hydroxycamptothecin (SN38), which

is subsequently glucuronidated by hepatic uri-

dine diphosphate glucuronosyltransferase-1A1

(UDP-GT 1A1) to SN38-glucuronide (SN38G)

as depicted in Figure 1 [Voigt et al. 1998; Gibson

and Stringer, 2009].

Both SN-38 and SN-38G are excreted via urine

and bile. Mass balance studies using 14car-

bonlabelled irinotecan have demonstrated thatthe fecal route of excretion is the major route

eliminating 63.7% of the administered drug.

SN38G, once in the intestinal lumen, is deconju-

gated by bacterial -glucuronidase to SN38. In

feces, SN38 was found to be in excess relative to

SN38G, which is suggestive of substantial

-glucuronidase activity in the human intestinal

contents [Saliba et al. 1998; Stringer et al. 2008].

The free intestinal luminal SN38, either from bile

or SN38G deconjugation, is responsible for

irinotecan-induced diarrhea. The different

mechanisms in detail by which the free SN38

induces diarrhea are still a matter of debate

[Stringer et al. 2007].

In summary the different mechanisms are dis-

cussed as follows:

(1) Free intestinal luminal SN38 induces directmucosal damage with water and electrolytemalabsorption and mucous hypersecretionin rats [Takasuna et al. 1995].

(2) The luminal environment is alteredby irinotecan and as a result may favordifferent genera of bacteria, allowing them

Table 2. Common Toxicity Criteria (version 3.0 and 4.02) for diarrhea, adapted from the National Cancer Institute.

Grade

1 2 3 4 5

Diarrhea(version 3.0)

Increase of

to proliferate. The bacterial -glucuronidasethen deconjugates SN38G to the activeform SN38 at an increased rate causing sig-nificant damage and diarrhea. [Takasunaet al. 1998; Stringer et al. 2007, 2008].

(3) The distribution and severity of histologicaldamage within the rat intestine after admin-istration of irinotecan has been correlatedto the luminal -glucuronidase activity inrodents [Takasuna et al. 1998; Fittkauet al. 2004].

(4) Irinotecan causes severe colonic damage(increased apoptosis, crypt hypoplasia anddilation) with accompanying excessivemucous secretion, as well as the usualchemotherapy-induced small intestinaldamage, like villous atrophy and crypt hypo-plasia. Increased levels of cell apoptosiscombined with the histopathologicalchanges in both the jejunum and colonand the changes in goblet cell numbersmay cause changes in absorption rates,possibly leading to diarrhea [Gibson et al.2003].

(5) Irinotecan causes an increase in mucinsecretion, accompanied by a significantdecrease of mucin expression in the jejunumand colon of rats shown by immunohisto-chemistry for Muc2 and Muc4. Thereforethe increase of mucin secretion is likely tobe related to altered mucine gene expres-sion, and may contribute to diarrheainduced by irinotecan [Stringer et al. 2009].

Molecular factors predictive ofirinotecan-induced toxicitiesConsidering the complex metabolism of irinote-

can (Figure 1) there are a couple of molecular

factors that are potentially predictive for

toxicities. There is no established factor for the

prediction of irinotecan-induced diarrhea yet.

However, pharmacogenomic research revealed a

predictive factor for hematologic toxicities, the

UGT isoform, UDP-glucuronosyltransferase,

or UGT1A1. UGT1A1 was one of the first fac-

tors to be investigated, due to the observation of

severe toxicities in patients with inherited disor-

ders characterized by decreased bilirubin glucur-

onidation like Gilberts syndrome (i.e. mild

unconjugated hyperbilirubinemia) [Wasserman

et al. 1997a]. Patients with homozygosity for

UGT1A1*28 allele have lower UGT1A1 expres-

sion, a decreased SN-38 glucuronidation and

therefore a higher risk for developing severe iri-

notecan toxicities. [Iyer et al. 2002; Innocenti

et al. 2004]. Regarding a frequency of around

9% for the homozygous allele, every tenth patient

has an enhanced risk for hematological toxicities,

leading to the approval of a genotyping method

by the US Food and Drug Administration in

2005. [Hoskins et al. 2007; Kim et al. 2007].

A recommendation for an upfront dose reduction

in this group of patients was added to the irino-

tecan package insert. However, recent studies

reveal varying results regarding the need for

Hepatic cell membrane

Irinotecan

Irinotecan

SN-38 SN-38G

M4, APC, NPC

SN-38G

SN-38

CES1CES2

SLC01B1 ABCC1

CYP3A4 CYP3A5

UGT1A1 UGT1A9

Via blood

ABCB1 ABCC2 ABCG2

ABCB1 ABCC2

Bacterial -glucuronidase

UGT1A1 UGT1A10

SN-38

Via bile excretedto the intestine

Figure 1. Metabolism of irinotecan. UGT, UDP glucuronosyltransferase; SN-38, 7-ethyl-10-hydroxycamp-tothecin;, CYP, cytochrome P450;, CES carboxylesterases; APC, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin; NPC, 7-ethyl-10-(4-amino-1-piperidino)carbonyloxy-camptothecin; M,oxidized metabolite; ABCB/C, ATP-binding cassette, sub-family B/C.



dose reductions during irinotecan treatment in

case of UGT1A1*28 genotype. In a retrospective

analysis of the Dutch CAIRO trial, a reduced

performance status and not the UGT1A1*28

genotype was a predictor for febrile neutropenia

in a bivariate analysis [Kweekel et al. 2008;

Liu et al. 2008].

Recently, the role of other UGT1A1 polymorph-

isms and genetic variations of SLCO1B1 and

ABC-transporters were investigated, with the

latter playing a pivotal role in the excretion of

SN-38 in the active form into the blood and in

the glucuronidated form into the bile (Figure 1)

[De Jong et al. 2007; Han et al. 2009; Innocenti

et al. 2009]. The variability of the ABCC2 gene

seems to be a determinant for irinotecan induced

diarrhea. However, the clinical relevance of these

factors still has to be determined. Further

research to establish predictive factors for daily

practice is absolutely essential.

Fluoropyrimidines (5-FU, capecitabine,tegafur/uracil)The severity and prevalence of diarrhea caused

by 5-FU treatment is increased by the addition

of leucovorin (LV) to the treatment regimen.

Diarrhea is reported in up to 50% of patients

receiving weekly 5-FU/LV combined treatment.

Moreover, the severity of the diarrhea can

increase when 5-FU is administered by bolus

injection as opposed to intravenous infusion

[Vincenzi et al. 2008]. Clinical factors predictive

for fluoropyrimidine-induced diarrhea are female

sex, caucasian race and presence of diabetes

[Zalcberg et al. 1998; McCollum et al. 2002;

Meyerhardt et al. 2004]. The gender- and

race-related differences are possibly influenced

by the variable activity of dihydropyrimidine-

dehydrogenase (DPD) [Mattison et al. 2006a].

The leading polymorphism, which accounts for

nearly 50% of nonfunctional alleles, is the

DPYD*2A, resulting in a decreased drug clear-

ance and prolonged exposure with severe toxici-

ties. Complete DPD deficiency is extremely rare,

but a partial deficiency is present in 35% of allcancer patients. DPD activity can be evaluated by

peripheral blood mononuclear cell radioassay,

DPD radioassaygenotyping of DPYD gene by

denaturing high performance liquid chromatog-

raphy (DHPLC), or 2-13C uracil breath test

(UraBT). The current genotyping strategies are

not yet available for routine use [Yen and

McLeod, 2007]. Potentially, the simple breath

test (UraBT) could be used as a screening tool

[Mattison et al. 2006b].

Of further predictive value are polymorphisms of

the thymidilate synthase (TS) and methylenete-

trahydrofolate reductase (MTHFR) genes.

However, taking into account the multifactorial

nature of fluoropyrimidine induced diarrhea, in

daily practice genotyping for DPD will be

initiated after occurrence of unusual toxicity.

Pathophysiology of fluoropyrimidine-induceddiarrheaAlthough 5-FU is routinely used in the treatment

of cancer and is known to cause diarrhea, very

few basic research papers have attempted to elu-

cidate the mechanisms underlying the pathophy-

siology. Early investigations revealed 5-FU being

the causative agent for mitotic arrest of intestinal

crypt cells, decrease of the relative fraction of vil-

lous enterocytes and the surface area for resorp-

tion [Siber et al. 1980]. Further research focused

on different dose schedules of this cytotoxic agent

using 5-FU in animal models [Cao et al. 1998].

Incidence of diarrhea with molecularlytargeted agents

Epidermal growth factor receptor-targetedtherapiesThe rate of severe diarrhea (grade 3/4) with epi-

dermal growth factor receptor (EGFR) targeting

therapies is less than 10%. For monoclonal anti-

bodies (mAb), such as the chimeric IgG1 mAb

cetuximab or the fully human IgG2 mAb panitu-

mumab, rates of grade 2 diarrhea are up to 21%

and for grade 3 (ie greater than 7 stools per day

or requiring intravenous fluids) between 1 and

2% [Van Cutsem et al. 2007; Davila and

Bresalier, 2008; Vincenzi et al. 2008]. Diarrhea

is more common in patients receiving small mol-

ecule EGFR tyrosine kinase inhibitors (TKIs),

such as erlotinib, gefitinib or lapatinib.

Occurrence of diarrhea is up to 60% for all

grades. Grade 3 diarrhea develops in about

69%. However, dose reduction due toEGFR-targeting therapy induced diarrhea is

seldom necessary. In combination with radiother-

apy diarrhea could be a more serious problem for

EGFR-targeting drugs.

Multitargeting tyrosine kinase inhibitorsSorafenib and sunitinib cause diarrhea in

3050% of patients (all grades) with a rate ofless than 10% of grade 3 diarrhea [Llovet et al.

A Stein, W Voigt et al.


2008; Gore et al. 2009; Motzer et al. 2009].

Imatinib, an inhibitor of the Bcr-Abl protein tyr-

osine kinase, causes diarrhea in about 30% of the

patients, but severe diarrhea is also rare.

m-TOR inhibitorsEverolimus and temsirolimus (inhibitors of the

mammalian target of rapamycin [m-TOR])

were both recently approved for treatment of

renal cell cancer, causing diarrhea in up to 40%

with a rate of severe diarrhea in less than 5% of

patients [Hudes et al. 2007; Motzer et al. 2008;

Hess et al. 2009].

Pathophysiology of molecularly targetedagent-induced diarrheaThe mechanisms of targeted agent-induced diar-

rhea are not adequately investigated yet. The

antitumor activity is based on apoptosis induc-

tion, antiangiogenesis and tyrosine kinase inhibi-

tion by targeting receptors or signaling pathways

that are present in normal cells as well, including

the mucosa. Increased levels of EGFR are found

in inflamed mucosa, particulary in goblet cells,

which seem to play a role in CID [Threadgill

et al. 1995]. However, there was no increase in

toxicity of head and neck radiation by addition of

cetuximab in a phase III trial despite a possible

correlation between EGFR targeting and matu-

ration of squamous eptithelium of the tongue and

nasal cavity [Bonner et al. 2006; Keefe and

Gibson, 2007]. The high expression of Kit in

the interstitial cells of Cajal, which function as

pacemaker cells of the intestinal motility, might

be a potential mechanism for diarrhea induced by

imatinib or sunitinib [Deininger et al. 2003].

Regarding the increasing utilization of targeted

therapies further research to gain the ability to

prevent diarrhea is urgently warranted [Keefe

and Anthony, 2008].

Therapeutic approachesThe treatment of CID includes nonpharmacolo-

gic and pharmacologic interventions to control

diarrhea and careful serial evaluation to rule out

significant volume depletion or comorbidities

that would require specific intervention or hospi-

talization [Benson et al. 2004; Maroun et al.

2007]. Initial nonpharmacologic measures

include avoidance of foods that would aggravate

the diarrhea and aggressive oral rehydration with

fluids that contain water, salt, and sugar

[Dupont, 1997]. These principles are similar to

those used for infectious diarrhea.

Given the lack of predictability for CID, signifi-

cant effort has been made to evaluate prophylac-

tic and therapeutic measures to reduce its

severity. A broad variety of drugs have been

tested for those measures.

Prophylactic measures

Antibiotics. Based on the assumption that bacte-rial -glucuronidase in the intestine is essential

for activating SN-38G which plays a crucial

role in the development of irinotecan-induced

mucosal damage, the eradication of bacteria

with marginally absorbable antibiotics, like neo-

mycin, seems to be an interesting approach

[Kehrer et al. 2001]. Despite promising results

in a small series for secondary prophylaxis

[Schmittel et al. 2004], a recent randomized

phase II study displayed only a nonsignificant

reduction of grade 3 diarrhea from 32.4 to

17.9% [De Jong et al. 2006]. In contrast, in a

further nonrandomized study with 51 patients

using levofloxacin just one patient experienced

grade 3 diarrhea with no grade 4 at all [Flieger

et al. 2007]. Regarding these controversial

results, the role of antibiotics in prevention of

irinotecan-induced diarrhea has to be further

investigated.

Budesonide. Pathophysiologically, the reductionof inflammation in the bowel could possibly

reduce the occurrence of diarrhea. The published

data however, only reveal a trend towards a reduc-

tion of CID from 4.2 to 1.8 days in a randomized

phase II study when concomitantly loperamide

was used [Karthaus et al. 2005]. In contrast,

in loperamide-refractory patients the CID grade

could be reduced in more than half of the

patients treated with either irinotecan or 5-FU

in a small case series [Lenfers et al. 1999].

Larger studies are necessary to determine the

actual role of budesonide.

Glutamine. Preclinical data suggests that gluta-mine stimulates intestinal mucosa growth, dis-

playing less gastrointestinal toxictiy in rodents

treated with chemotherapy [Fox et al. 1988;

Xue et al. 2008]. Results from randomized stu-

dies showed a nonsignificant reduction in the

CID rate [Daniele et al. 2001], and no effect in

the prevention of radiation-induced diarrhea for

the oral application form of glutamine was

revealed [Kozelsky et al. 2003]. Importantly,

a trial in patients receiving high-dose chemo-

therapy and glutamine-containing intravenous



solutions showed significantly more relapses and

deaths in the glutamine group [Pytlik et al. 2002].

Recently, a series with 44 patients showed a sig-

nificant reduction in diarrhea with prophylactic

use of intravenous glutamine any influence

on survival was not reported [Li et al. 2009].

Considering these results, a further development

of glutamine for CID seems to be questionable.

Celecoxib. In animal models, celecoxibenhanced the antitumor activity of irinotecan

and reduced the rate of diarrhea [Trifan et al.

2002]. The rate of grade 3 diarrhea was only

8% in one trial of 43 patients suffering from

malignant gliomas treated with irinotecan and

celecoxib [Reardon et al. 2005], whereas in

another study with the same sample size using a

combination of celecoxib and glutamine with

the IFL-regimen the rate was 45% for grade 3

diarrhea, which is even higher than the expected

margin [Pan et al. 2005]. In a recent review, no

improvement with the usage of celecoxib in redu-

cing CID was observed in the analyzed studies

[Fakih and Rustum, 2009].

Long-acting formulation of octreotide. The effi-cacy of long-acting octreotide in the therapeutic

setting has been demonstrated, as has its use in

secondary prophylaxis in a small case series with

doses ranging from 20mg up to 40mg every

4 weeks [Rosenoff, 2004a,b]. A large randomized

study resulted in a nonsignificant reduction of

severe diarrhea (61.7 versus 48.4%) favoring a

dose of 40mg over 30mg every 4 weeks as

secondary prophylaxis [Rosenoff et al. 2006].

However, preliminary results of a study presented

by Zacchariah and colleagues at ASCO 2007 in

the primary prophylaxis of diarrhea in 215 rectal

cancer patients receiving 5-FU based chemora-

diation was negative, revealing no difference

between placebo and 30mg of long-acting

octreotide [Zachariah et al. 2007]. In patients

receiving pelvic radiation the prophylactic treat-

ment with 20mg of long-acting octreotide versus

placebo showed even worse tolerability regarding

gastrointestinal symptoms and no change in diar-

rhea [Martenson et al. 2008].

Probiotics. Probiotics have been shown to pre-vent diarrhea in inflammatory bowel disease.

Preclinical data yielded a similar efficacy in

CID [Von Bultzingslowen et al. 2003; Bowen

et al. 2007]. In the clinical setting, a combination

of Lactobacillus rhamnosus and fiber resulted in

a significant reduction of grade 3/4 diarrhea

(37 versus 22%) in a randomized study of patients

treated with either bolus (Mayo) or bolus and

infusional (simplified de Gramont) 5-FU with

leucovorin for adjuvant treatment of colorectal

cancer [Osterlund et al. 2007].

Activated charcoal. The prophylactic use of acti-vated charcoal in irinotecan-induced diarrhea

seems to have interesting potential. Two small

studies, one conducted in children, displayed a

reduction in grade 3/4 diarrhea (7.1 versus 25%

and 4.4 versus 52.3%) with excellent compliance

and tolerability. The discontinuation rate of iri-

notecan was much lower and less loperamide was

used [Michael et al. 2004; Sergio et al. 2008].

This approach should be further investigated in

a phase III trial.

A further possible approach is the modulation of

irinotecan pharmacokinetics, by the addition

of phenobarbital, phenytoin and cyclosporine,

to downsize SN-38 biliary excretion and induce

glucuronidation, limited by the small therapeutic

range of the used drugs and the possible decre-

mental impact on efficacy, due to reduced con-

centration of active metabolites. Attempts have

also been made to pharmacologically upregulate

intestinal mucosal UDP-GT 1A1 with the plant

flavonoid, chrysin. Other therapeutic measures

assessed include an encephalinase inhibitor (acet-

orphan), which seems to be equally effective

as loperamide in the treatment of non-CID

diarrhea.

Guideline-based drug recommendationsSo far, only loperamide, octreotide and tincture

of opium are recommended in the updated treat-

ment guidelines by the consensus conference on

the management of CID from Benson and col-

leagues due to a lack of efficacy or insufficient

evidence level of the other mentioned therapeutic

approaches [Benson et al. 2004].

OpioidsLoperamide is an opioid which functions by

decreasing intestinal motility by directly affecting

the smooth muscle of the intestine and has no

systemic effects due to a minimal absorption.

The recommendation in current treatment

guidelines [Benson et al. 2004] is based on an

effective reduction in fecal incontinence, fre-

quency of bowel movements and stool weight.

The dosage of loperamide is an initial 4mg

dose followed by 2mg every 24 hours or after



every unformed stool. In case of CID, especially

irinotecan-containing therapies, the more aggres-

sive regimen should be chosen.

Deodorized tincture of opium (DTO) is another

widely used antidiarrheal agent, despite the

absence of literature to support its use in CID

treatment. DTO contains the equivalent of

10mg/ml morphine. The recommended dose is

1015 drops in water every 34 hours [Bensonet al. 2004]. The camphorated (alcohol-based)

tincture is a less concentrated preparation con-

taining the equivalent of 0.4mg/ml morphine,

leading to a dose of 5ml (one teaspoon) every

34 hours.

OctreotideOctreotide, a synthetic somatostatin analog, acts

via several mechanisms: decreased secretion of a

number of hormones, such as vasoactive intesti-

nal peptide (VIP); prolongation of intestinal tran-

sit time and reduced secretion and increased

absorption of fluid and electrolytes. It is approved

by the US Food and Drug Administration for the

treatment of diarrhea related to VIP-secreting

tumors and symptoms due to carcinoid syn-

drome. Octreotide is beneficial in patients with

CID from fluoropyrimidines, irinotecan, and

5-FU-based chemoradiotherapy [Gebbia et al.

1993; Goumas et al. 1998; Barbounis et al.

2001]. Although one randomized trial in 41

5-FU-treated patients showed that octreotide

was more effective than standard-dose lopera-

mide (90 versus 15% resolution of diarrhea by

day 3) [Cascinu et al. 1993], octreotide is gener-

ally reserved as a second-line treatment for

patients who are refractory after 48 hours, despite

a loperamide escalation, because of its high cost

[Zidan et al. 2001]. Patients developing a gastro-

intestinal syndrome including severe diarrhea,

nausea, vomiting, anorexia, and abdominal

cramping should receive an aggressive manage-

ment with intravenous fluids and upfront octreo-

tide. These recommendations by the consensus

conference mentioned above reflect the risk of

life-threatening complications and the reduced

activity of loperamide in cases of severe diarrhea

[Cascinu et al. 2000].

The optimal dosage of octreotide is not well

defined. Current treatment guidelines recom-

mend a starting dose of 100150mg subcuta-neously (sc) or intravenously (iv) three times

a day. Doses could be escalated to 500 mg sc/ivthree times a day or by continuous iv infusion

2550mg/hr showing a dose-response relation-ship without significant toxicities [Wadler et al.

1995; Wasserman et al. 1997b].

Summary of the consensus recommendationsThe recommendations of a consensus conference

on the management of CID were published

in 1998 and updated in 2004. Guidelines for

evaluation and management of patients with

CID are presented in Figure 2 [Wadler et al.

1998, Benson et al. 2004]. The tempo and

specific nature of treatment is guided by the

classification of the symptom constellation as

complicated or uncomplicated. Uncomplicated

patients may be managed conservatively in the

outpatient setting (at least initially), while those

with severe diarrhea or a potentially exacerbating

condition (eg abdominal cramping, nausea,

vomiting, fever, sepsis, neutropenia or bleeding)

should be admitted to the hospital and treated

aggressively with octreotide, intravenous fluids,

antibiotics and a diagnostic workup.

ConclusionCID is caused by changes in intestinal absorption

and might be accompanied by excessive electro-

lyte and fluid secretion. Furthermore, this type of

diarrhea may be a consequence of biochemical

changes caused by chemotherapy. Depending

on the chemotherapeutic regimen, rates of

severe or life-threatening CID can be up to

30% (grade 35 diarrhea), especially with 5-FUbolus or combination therapies of irinotecan and

fluoropyrimidines (IFL, XELIRI). Regarding the

tremendous effects on patients safety and quality

of life, the possible occurrence of CID has to be

carefully considered. Current research focuses

on establishing predictive factors for toxicities

caused by therapeutic agents like UGT1A1-

polymorphisms for irinotecan or DPD-

insufficiency for fluoropyrimidines. Despite the

amount of clinical trials evaluating therapeutic

or prophylactic measures in CID, there are just

three drugs recommended in current guidelines:

loperamide, deodorized tincture of opium and

octreotide. Further evaluation of treatment

options is absolutely essential for the manage-

ment of this debilitating toxicity.



EVALUATE

ADDED RISK FACTORS

MANAGEMENT

TREATMENT

Reassess 1224 hours later Diarrhea unresolvedProgression to severe diarrhea(NCI grades 34 with or withoutfever, dehydration, neutropenia,and/or blood in stool)

COMPLICATEDCTC grade 3 or 4 diarrhea

Obtain history of onset and duration of diarrhea

Assess patient for fever, dizziness, abdominal pain/cramping, or weakness (ie, rule out risk for sepsis, bowel obstruction, dehydration) Dietary profile (ie, to identify diarrhea-enhancing foods) Medications profile (ie, to identify diarrheogenic agents)

Describe number of stools and stool composition (eg, watery, blood in stool, nocturnal)

UNCOMPLICATEDCTC grade 1-2 diarrhea

with no complicatingsigns or symptoms

Cramping Nausea/vomiting ( grade 2) Decreased perofrmance stauts Fever Sepsis Neutropenia Frank bleeding Dehydration

or grade 1 or 2 with one ormore of the following signsor symtoms

Stop all lactose-containing products, alcohol, and high-osmolar supplements Drink 810 large glasses of clear liquids a day (eg, Gatorade or broth) Eat frequent small meals (eg, bananas, rice, appleasuce, toast, plain pasta) Instruct patient to record the number of stools and report symptoms of life-threatening sequelae (eg, fever or dizziness upon standing) For grade 2 diarrhea, hold cytotoxic chemotherapy unitl symptoms resolve and consider dose reduction

Administer standard dose of loperamide: initial dose 4 mg followed by 2 mg every 4 hours or after every unformed stool Consider clinical trial

Diarrhea resolving

Diarrhea resolving

Cotinue instructions for dietary modification

Cotinue instructions for dietary modification

Gradually add solid foods to diet

Gradually add solid foods to diet

Discontinue loperamide after 12-hour diarrhea-free interval

Discontinue loperamide after 12-hour diarrhea-free interval

RT-induced: continue loperamide

RT-induced: continue loperamide

Persistent diarrhea (NCI grades 12) Administer loperamide 2 mg every 2 hours Start oral antibiotics Observe patient for responseRT-induced: oral antibiotics not

generally recommended

Reassess 1224 hours later

Progression to severe diarrhea(NCI grades 34 with or withoutfever, dehydration, neutropenia,and/or blood in stool)

Diarrhea unresolved

ADMIT TO HOSPITAL

EVALUATE IN OFFICE/OUTPATIENT CENTER

Persistent diarrhea (NCI grades 12)(no fever, dehydration, neutropenia,and/or blood in stool)

Check stool workup(blood, fecal leukocytes, Clostridium difficile, Salmonella, Escherichia coli,Campylobacter, infectious colitis)

Check CBC and electrolytes Perform abdominal exam Replace fluids and electrolytes as appropriate Discontinue loperamide and begin second-line agent

Octreotide (100 to 150 g SC TID with dose escalation up to 500 g TID) Other second-line agent (eg, tincture of opium)

RT-induced: Continue loperamide or other oral agent; no workup required

Administer octreotide(100 to 150 g SC TID or IV (25-50 g/hr)if dehydration is severe with dose

as needed (eg, fluorogquinolone)

all symptoms resolve; restartchemotherapy at reduced dose

escalation up to 500 g TID) Start intravenous fluids and antibiotics

Stool work-up, CBC, and electrolyte profile Discontinue cytotoxic chemotherapy until

Figure 2. Consensus guideline for the treatment of chemotherapy induced diarrhea [Benson et al. 2004].Reprinted with permission ! 2008 American Society of Clinical Oncology. All rights reserved.



Conflict of interest statementNone declared.

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